Crystalline form of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide

ABSTRACT

The present invention is directed to a novel crystalline form of (2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide, pharmaceutical compositions containing said crystalline form and the use of said crystalline form in the treatment of anxiety and related disorders; bipolar depression and mania; depression; epilepsy and related disorders; epileptogenesis; glucose related disorders; lipid related disorders; migraine; obesity; pain; substance abuse; or for neuroprotection. The present invention is further directed to a process for the preparation of the novel crystalline form.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/074,783, filed on Jun. 23, 2008, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a novel crystalline form of(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide,pharmaceutical compositions containing said crystalline form and the useof said crystalline form in the treatment anxiety and related disorders;bipolar depression and mania; depression; epilepsy and relateddisorders; epileptogenesis; glucose related disorders; lipid relateddisorders; migraine; obesity; pain; substance abuse and as aneuroprotective agent. The present invention is further directed to aprocess for the preparation of the novel crystalline form.

BACKGROUND OF THE INVENTION

US Patent Publication US2006-0041008 A1, published Feb. 23, 2006discloses benzo-fused sulfamide derivatives useful for the treatment ofepilepsy and related disorders; US Patent Publication 2007-0293441 A1,published Nov. 18, 2008 discloses co-therapy for the treatment ofepilepsy and related disorder comprising administration of benzo-fusedsulfamide derivatives and on or more anticonvulsants and/oranti-epileptic agents; US Patent Publication US2007-0155826 A1,published Jul. 5, 2007 discloses the use of benzo-fused sulfamidederivatives for the treatment of bipolar disorder and mania; US PatentPublication US2007-0155827 A1, published Jul. 5, 2007 discloses the useof benzo-fused sulfamide derivatives for the treatment of depression; USPatent Publication US2007-0155824 A1, published Jul. 5, 2007 disclosesthe use of benzo-fused sulfamide derivatives for the treatment ofepileptogenesis; US Patent Publication US2007-0155821 A1, published Jul.5, 2007 discloses the use of benzo-fused sulfamide derivatives for thetreatment of glucose related disorders and for the treatment of lipidrelated disorders; US Patent Publication US2007-0191474 A1, publishedAug. 16, 2007 discloses the use of benzo-fused sulfamide derivatives forthe treatment of migraine; US Patent Publication US2007-015823 A1,published Jul. 5, 2007 discloses the use of benzo-fused sulfamidederivatives for neuroprotection; US Patent Publication US2008-0027131A1, published Jan. 31, 2008 discloses the use of benzo-fused sulfamidederivatives for the treatment of obesity; US Patent PublicationUS2007-0155822 A1, published Jul. 5, 2007 discloses the use ofbenzo-fused sulfamide derivatives for the treatment of pain; US PatentPublication US2007-0155825 A1, published Jul. 5, 2007 discloses the useof benzo-fused sulfamide derivatives for the treatment of substanceabuse and/or addiction; which are herein incorporated by reference intheir entirety.

SUMMARY OF THE INVENTION

The present invention is directed to a novel crystalline form of thecompound of formula (IS)

also known as(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide.The novel crystalline form of the compound of formula (IS), hereinafterreferred to as crystalline form (IS-VI), may be characterized, forexample, by its X-ray diffraction pattern.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and crystalline form (IS-VI). Anillustration of the invention is a pharmaceutical composition made bymixing crystalline form (IS-VI) and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing crystalline form (IS-VI)and a pharmaceutically acceptable carrier.

The present invention is further directed to methods for the treatmentof anxiety and related disorders; bipolar depression and mania;depression; epilepsy and related disorders; epileptogenesis; glucoserelated disorders; lipid related disorders; migraine; obesity; pain;substance abuse or neuroprotection comprising administering to a subjectin need thereof a therapeutically effective amount of crystalline form(IS-VI).

Another example of the invention is the use of crystalline form (IS-VI)in the preparation of a medicament for treating: (a) anxiety and relateddisorders; (b) bipolar depression (c) mania; (d) depression; (e)epilepsy and related disorders; (f) epileptogenesis; (g) glucose relateddisorders; (h) lipid related disorders; (i) migraine; (j) obesity; (k)pain; (l) substance abuse and (m) for neuroprotection, in a subject inneed thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a representative powder XRD pattern of crystallineform (IS-VI) for the compound of formula (IS), measured as describedherein.

FIG. 2 illustrates a representative DSC for crystalline form (IS-VI) ofthe compound of formula (IS), measured as described herein.

FIG. 3 illustrates a representative TGA scan for crystalline form(IS-VI) of the compound of formula (IS), measured as described herein.

FIG. 4 illustrates a representative DVS scan for crystalline form(IS-VI) of the compound of formula (IS), measured as described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel crystalline form of thecompound of formula (IS)

herein referred to as crystalline form (IS-VI). The present invention isfurther directed to the use of crystalline form (IS-VI) for thetreatment of anxiety and related disorders; bipolar depression andmania; depression; epilepsy and related disorders; epileptogenesis;glucose related disorders; lipid related disorders; migraine; obesity;pain; substance abuse and for neuroprotection. The present invention isfurther directed to pharmaceutical compositions comprising crystallineform (IS-VI).

Where the compound according to this invention has at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%.

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, crystalline form(IS-VI) is present as an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound or crystalline form is less than about 5 mole percent,preferably less than about 2 mole percent, more preferably, less thanabout 0.5 mole percent, most preferably, less than about 0.1 molepercent. In an embodiment of the present invention, crystalline form(IS-VI) is present as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofother polymorph or crystalline form(s)” when used to described thecompound of formula (I) shall mean that mole percent of other polymorphor crystalline form(s) in the isolated base of formula (I) is less thanabout 5 mole percent, preferably less than about 2 mole percent, morepreferably, less than about 0.5 mole percent, most preferably less thanabout 0.1 mole percent. In an embodiment of the present invention,crystalline form (IS-VI) is present as a form substantially free ofother polymorph or crystalline form(s).

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

As used herein, the terms “anxiety and related disorders” and “anxietyor a related disorder” shall be defined to include anxiety and relateddisorders including generalized anxiety disorder, acute stress disorder,post traumatic stress disorder, obsessive-compulsive disorder, socialphobia (also known as social anxiety disorder), specific phobia, panicdisorder with or without agoraphobia, agoraphobia without a history ofpanic disorder, anxiety disorder due to general medical condition,substance abuse induced anxiety disorder and anxiety disorder nototherwise specified (as these conditions are described by theirdiagnostic criteria, as listed in the Diagnostic and Statistical Manualof Mental Disorders, 4^(th) Edition, Text Revision, American PsychiatricAssociation, 2000, incorporated herein by reference). Preferably, theanxiety or related disorder is selected from the group consisting ofgeneralized anxiety disorder, acute stress disorder, post traumaticstress disorder and obsessive-compulsive disorder. More preferably, theanxiety and related disorder is generalized anxiety disorder.

Bipolar disorder is psychiatric disorder characterized by unpredictableswings in mood from mania (or hypomania) to depression. As used herein,the term “bipolar disorder” shall include bipolar disorder I, bipolardisorder II, cyclothymic disorder and bipolar disorder not otherwisespecified. Preferably, the bipolar disorder is characterized bydepressive and manic (or hypomanic) phases, wherein the phases cycle.Preferably, the bipolar disorder is bipolar disorder I or bipolardisorder II.

As used herein, the term “bipolar depression” is intended to mean thedepression associated with, characteristic of or symptomatic of abipolar disorder. Thus, methods of treating bipolar depression of thepresent invention are directed to methods which treat the depressionand/or depressed phase of bipolar disorders.

As used herein, unless otherwise noted the terms “cycling” or “bipolarcycling” shall refer to the alternation of mood between depressive andmanic phases characteristic of bipolar disorders. Thus, the presentinvention includes methods for the stabilization of said cycling,including, but not limited to, decreasing the frequency of the cyclingand/or decreasing the magnitude of the manic and/or depressive phases.

As used herein, the term “mania” shall include mania or a manic moodphase, regardless of underlying cause. As used herein, the term “bipolarmania” is intended to mean the mania associated with, characteristic ofor symptomatic of a bipolar disorder. Thus, methods of treating bipolarmania of the present invention are directed to methods which treat themania and/or manic phase of bipolar disorders.

As used herein, the term “depression” shall be defined to include majordepressive disorder (including single episode and recurrent), unipolardepression, treatment-refractory depression, resistant depression,anxious depression and dysthymia (also referred to as dysthymicdisorder). Further, the term “depression” shall encompass any majordepressive disorder, dysthymic disorder and depressive disorder nototherwise specific as defined by their diagnostic criteria, as listed inthe Diagnostic and Statistical Manual of Mental Disorders, 4^(th)Edition, Text Revision, American Psychiatric Association, 2000.Preferably, the depression is major depressive disorder, unipolardepression, treatment-refractory depression, resistant depression oranxious depression. More preferably, the depression is major depressivedisorder.

As used herein, unless otherwise noted, the terms “epilepsy and relateddisorders” or “epilepsy or related disorder” shall mean any disorder inwhich a subject (preferably a human adult, child or infant) experiencesone or more seizures and/or tremors. Suitable examples include, but arenot limited to, epilepsy (including, but not limited to,localization-related epilepsies, generalized epilepsies, epilepsies withboth generalized and local seizures, and the like), seizures as acomplication of a disease or condition (such as seizures associated withencephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg'sprogressive myoclonic epilepsy, stroke, head trauma, stress, hormonalchanges, drug use or withdrawal, alcohol use or withdrawal, sleepdeprivation, and the like), essential tremor, restless limb syndrome,and the like. Preferably, the disorder is selected from epilepsy(regardless of type, underlying cause or origin), essential tremor orrestless limb syndrome, more preferably, the disorder is epilepsy(regardless of type, underlying cause or origin) or essential tremor.

As used herein, the term “epileptogenesis” shall mean the biochemical,genetic, histological or other structural or functional processes orchanges that make nervous tissue, including the central nervous system(CNS) susceptible to recurrent, spontaneous seizures. In addition, theterm “epileptogenesis” is also used herein in a broader sense to referto the changes and/or processes that contribute to the clinicalprogression observed in patients with epilepsy or other seizure disorderor an analogous seizure-related disorder including but not limited to;the worsening or progression of the disorder and it's symptoms or thedevelopment of “pharmacoresistance,” in which the disorder becomes moredifficult to treat as a result of neurobiological changes which resultin reduced drug sensitivity or the recruitment by the process ofepileptogenesis of non seizure prone nervous tissue. Furthermore theterm “epileptogenesis” is used herein in the broadest possible sense torefer to the similar phenomena of progressive worsening over time of thesigns and symptoms of apparently non-epileptic disorders, includingpsychiatric disorders the etiology of which appear to be seizurerelated.

Epileptogenesis is a Two Phase Process: “Phase 1 epileptogenesis” is theinitiation of the epileptogenic process prior to the first epilepticseizure or symptom of an analogous seizure-related disorder, and isoften the result of some kind of injury or trauma to the brain, i.e.,stroke, disease (e.g., infection such as meningitis), or trauma, such asan accidental blow to the head or a surgical procedure performed on thebrain. “Phase 2 epileptogenesis” refers to the process during whichbrain tissue that is already susceptible to epileptic seizures orseizure related phenomena of an analogous seizure-related disorder,becomes still more susceptible to seizures of increasing frequencyand/or severity and/or becomes less responsive to treatment.

As used herein, the term “glucose related disorder” shall be defined asany disorder which is characterized by elevated glucose levels. Glucoserelated disorders include elevated glucose level, pre-diabetes, impairedoral glucose tolerance, poor glycemic control, Type II DiabetesMellitus, Syndrome X (also known as metabolic syndrome), gestationaldiabetes, insulin resistance, hyperglycemia and loss of muscle mass as aresults of hyperglycemia (cachexia).

Treatment of glucose related disorders may comprise lowering glucoselevels, improving glycemic control, decreasing insulin resistance and/orpreventing the development of a glucose related disorder (for examplepreventing a patient suffering from impaired oral glucose tolerance orelevated glucose levels from developing Type II diabetes mellitus).

As used herein, the term “lipid related disorder” shall be defined asany disorder which is characterized by non-normal lipid levels. Lipidrelated disorders include elevated triglyceride levels, low HDLcholesterol and dyslipidemia, preferably elevated triglyceride levels orlow HDL cholesterol levels Treatment of lipid related disorder maycomprise lowering triglycerides, elevating HDL cholesterol and/orimproving the triglyceride/HDL ratio.

As used herein, the term “migraine” shall mean a chronic, episodic anddebilitating clinical condition that is diagnosed by the presence ofmoderate to severe pulsating unilateral headaches lasting between 4 and72 h, which includes migraine without aura and migraine with aura.

As used herein, “migraine without aura” shall mean at least five attacksfulfilling the following criteria: (a) the headache attack lasts 4-72hours with the headache having at least two of the following features:unilateral location, pulsating quality, moderate or severe intensitywith direct influence on activities of daily living, and aggravation bywalking up stairs or similar routines; and (b) during the headache atleast one of the following occurs: nausea and/or vomiting, andphotophobia and phonophobia.

As used herein, “migraine with aura” shall mean at least two attacksaccompanied by at least 3 of the 4 following features: (a) one or morefully reversible aura symptoms; (b) at least one aura symptom whichdevelops gradually over more than four minutes or two or more symptomswhich occur in succession; (c) no aura symptom which lasts more than 60minutes; (d) a headache occurs prior to, simultaneously with orfollowing the aura, with a free interval between aura and headache ofless than about 60 minutes.

As used herein, the term “prevention” shall include the prevention ofmigraine attacks (headaches), a decrease in the frequency of migraineattacks (headaches), a decrease in the severity of migraine attacks(headaches) and/or a decrease in the duration of migraine attacks(headaches).

As used herein, the term “obesity” shall be defined as a body mass index(BMI) of greater than or equal to about 25, preferably a BMI of greaterthan or equal to about 30. Thus as used herein, the term “obesity” shallinclude both overweight and clinically obese subjects/patients.

As used herein, the term “pain” shall be defined to include acute,chronic, inflammatory and neuropathic pain (preferably diabeticneuropathy). Further, the pain may be centrally mediated, peripherallymediated, caused by structural tissue injury, caused by soft tissueinjury or caused by progressive disease. Any centrally mediated,peripherally mediated, structural tissue injury, soft tissue injury orprogressive disease related pain may be acute or chronic.

As used herein, unless otherwise noted, pain shall include inflammatorypain, centrally mediated pain, peripherally mediated pain, visceralpain, structural related pain, cancer pain, soft tissue injury relatedpain, progressive disease related pain, neuropathic pain, acute painfrom acute injury, acute pain from trauma, acute pain from surgery,headache, dental pain, back pain (preferably lower back pain), chronicpain from neuropathic conditions and chronic pain from post-strokeconditions.

In an embodiment of the present invention, is a method for the treatmentof pain, wherein the pain is acute pain. In another embodiment of thepresent invention, is a method for the treatment of pain, wherein thepain is chronic pain. In another embodiment of the present invention, isa method for the treatment of pain, wherein the pain is neurpoathicpain, more preferably diabetic neuropathy. In yet another embodiment ofthe present invention, is a method for the treatment of pain, whereinthe pain is inflammatory pain.

In an embodiment, the pain is selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, headache, toothache,burn, sunburn, animal bite (such as dog bite, cat bite, snake bite,spider bite, insect sting, and the like), neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, cellulites, causalgia, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limbpain, post-operative ileus, cholecystitis, postmastectomy pain syndrome,oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome,post-herpetic neuralgia, trigeminal neuralgia, peripheral neuropathy,bilateral peripheral neuropathy, diabetic neuropathy, postherpeticneuralgia, trigeminal neuralgia, optic neuritis, postfebrile neuritis,migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidianneuralgia, inflammatory bowel disease, irritable bowel syndrome, labor,childbirth, menstrual cramps, cancer, back pain, lower back pain andcarpal tunnel syndrome pain.

Acute pain includes pain caused by acute injury, trauma, illness orsurgery (for example, open-chest surgery (including open-heart or bypasssurgery)). Acute pain also includes, and is not limited to, headache,post-operative pain, kidney stone pain, gallbladder pain, gallstonepain, obstetric pain, rheumatological pain, dental pain or pain causedby sports-medicine injuries, carpal tunnel syndrome, burns,musculoskeletal sprains and strains, musculotendinous strain,cervicobrachial pain syndromes, dyspepsia, gastric ulcer, duodenalulcer, dysmenorrhea or endometriosis.

Chronic pain includes pain caused by an inflammatory condition,osteoarthritis, rheumatoid arthritis or as sequela to disease, acuteinjury or trauma. Chronic pain also includes, and is not limited to,headache, upper back pain or lower back pain (selected from back painresulting from systematic, regional or primary spine disease (selectedfrom radiculopathy)), bone pain (selected from bone pain due toosteoarthritis, osteoporosis, bone metastases or unknown reasons),pelvic pain, spinal cord injury-associated pain, cardiac chest pain,non-cardiac chest pain, central post-stroke pain, myofascial pain,cancer pain, AIDS pain, sickle cell pain, geriatric pain or pain causedby headache, migraine, trigeminal neuralgia, temporomandibular jointsyndrome, fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis,gout, fibrositis or thoracic outlet syndromes.

Neuropathic pain includes pain resulting from chronic or debilitatingconditions or disorders. The chronic or debilitating conditions ordisorders which can lead to neuropathic pain include, but are notlimited to, painful diabetic peripheral neuropathy, post-herpeticneuralgia, trigeminal neuralgia, post-stroke pain, multiplesclerosis-associated pain, neuropathies-associated pain such as inidiopathic or post-traumatic neuropathy and mononeuritis, HIV-associatedneuropathic pain, cancer-associated neuropathic pain, carpaltunnel-associated neuropathic pain, spinal cord injury-associated pain,complex regional pain syndrome, fibromyalgia-associated neuropathicpain, lumbar and cervical pain, reflex sympathic dystrophy, phantom limbsyndrome and other chronic and debilitating condition-associated painsyndromes.

As used herein, the term “treatment of substance abuse” shall includetreatment of substance abuse or addiction, including but not limited tothe treatment of carvings, withdrawal, and other symptoms of addictionor abuse. As used herein, unless otherwise noted the term “substance”when referring to substances of abuse and/or addiction shall include anylegal or illegal substance to which a subject or patient may develop anaddiction. Suitable examples include, but are not limited to alcohol,cocaine, heroine, methamphetamine, ketamine, Ecstacy, nicotine,oxycontin/oxycodone, codeine, morphine, and the like.

As used herein, the term “neuroprotection” shall mean the protectingneurons in the brain, central nervous system or peripheral nervoussystem (preferably in the brain or spinal cord) from death and/ordamage. Preferably, the neurons are protected from death or damagecaused by oxidative stress, for example oxygen radicals.

“Acute neurodegenerative disorders” included within the methods of thepresent invention include, but are not limited, to various types ofacute neurodegenerative disorders associated with neuron death or damageincluding cerebrovascular insufficiency, focal brain trauma, diffusebrain damage, and spinal cord injury, that is, cerebral ischemia orinfarction including embolic occlusion and thrombotic occlusion,reperfusion following acute ischemia, perinatal hypoxic-ischemic injury,cardiac arrest, as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration), and whiplash shaken infant syndrome. Preferably, the acuteneurodegenerative disorder is a result of stroke, acute ischemic injury,head injury or spinal injury.

“Chronic neurodegenerative disorders” included within the methods of thepresent invention included, but are not limited to, Alzheimer's disease,Pick's disease, diffuse Lewy body disease, progressive supranuclearpalsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Dragersyndrome), chronic epileptic conditions associated withneurodegeneration, motor neuron diseases including amyotrophic lateralsclerosis, degenerative ataxias, cortical basal degeneration,ALS-Parkinson's-Dementia complex of Guam, subacute sclerosingpanencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies (including multiple system atrophy), primaryprogressive aphasia, striatonigral degeneration, Machado-Josephdisease/spinocerebellar ataxia type 3 and olivopontocerebellardegenerations, Gilles De La Tourette's disease, bulbar and pseudobulbarpalsy, spinal and spinobulbar muscular atrophy (Kennedy's disease),multiple sclerosis, primary lateral sclerosis, familial spasticparaplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease,Tay-Sach's disease, Sandhoff disease, familial spastic disease,Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, familial dysautonomia (Riley-Daysyndrome), and prion diseases (including, but not limited toCreutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuru andfatal familial insomnia). Preferably, the chronic neurodegenerativedisorder is selected from Alzheimer's disease, Parkinson's disease,multiple sclerosis or cerebral palsy,

Other disorders which manifest neuron death or damage and as such areintended to be included within the methods of the present inventioninclude dementias, regardless of underlying etiology, includingage-related dementia and other dementias and conditions with memory lossincluding dementia associated with Alzheimer's disease, vasculardementia, diffuse white matter disease (Binswanger's disease), dementiaof endocrine or metabolic origin, dementia of head trauma and diffusebrain damage, dementia pugilistica and frontal lobe dementia.

Also included within the present invention are methods ofneuroprotection (i.e. methods for the prevention of neuron death and/ordamage) following injury to the brain, central nervous system orperipheral nervous system, wherein the injury resulting from chemical,toxic, infectious, radiation and/or traumatic injury. Preferably, themethods of the present invention are directed to preventing neuron deathor damage following brain, head and/or spinal cord trauma or injury,regardless of cause.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

One skilled in the art will recognize that, in the specification andclaims as presented herein, wherein a reagent or reagent class/type(e.g. base, solvent, etc.) is recited in more than one step of aprocess, the individual reagents are independently selected for eachreaction step and may be the same of different from each other. Forexample wherein two steps of a process recite an organic or inorganicbase as a reagent, the organic or inorganic base selected for the firststep may be the same or different than the organic or inorganic base ofthe second step.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

Crystalline form (IS-VI) may be characterized by its powder X-raydiffraction pattern (pXRD). The powder XRD was measured for arepresentative sample of the crystalline form (IS-VI), as shown inFIG. 1. The sample was analyzed using an X'PERT PRO MPD x-raydiffractometer from Philips with a 16 mm backloaded holder; using theX-Celerator detector. The sample was scanned from 3 to 35° 2θ at a stepsize of 0.0165° 2θ and a time per step of 10.16 seconds. The effectivescan speed was 0.2067°/s; with instrument voltage and current settingsof 45 kV and 40 mA. The sample was analyzed using the divergence slit inautomatic mode and a beam knife in the fully down position was employed.

Crystalline form (IS-VI) may be characterized by its powder X-raydiffraction pattern, which comprised the peaks as listed in Table 1,below.

TABLE 1 pXRD Peaks, Crystalline Form (IS-VI) Pos. [° 2θ.] FWHM[° 2θ.]d-spacing[Å] Rel. Int. [%] 6.54 0.07 13.51 8 13.07 0.08 6.78 100 16.500.10 5.37 7 18.53 0.13 4.79 20 19.64 0.10 4.52 49 19.91 0.08 4.46 1320.17 0.10 4.40 6 21.15 0.13 4.20 18 22.09 0.10 4.02 12 22.52 0.12 3.958 23.51 0.10 3.79 9 26.28 0.08 3.39 6 27.56 0.15 3.24 7 28.20 0.12 3.178 33.60 0.07 2.67 6

Preferably, crystalline form (IS-VI) is characterized by its pXRDpattern which comprises peaks having a relative intensity greater thanor equal to about 10%, as listed in Table 2 below.

TABLE 2 pXRD Peaks, Crystalline Form (IS-VI) Pos. [° 2θ.] FWHM[° 2θ.]d-spacing[Å] Rel. Int. [%] 13.07 0.08 6.78 100 18.53 0.13 4.79 20 19.640.10 4.52 49 19.91 0.08 4.46 13 21.15 0.13 4.20 18 22.09 0.10 4.02 12

DSC (Differential Scanning Calorimetry) was measured for arepresentative sample of crystalline form (IS-VI), as shown in FIG. 2.DSC analysis of the sample was performed using a TA Instruments DSCQ1000 differential scanning calorimeter. The sample was analyzed asreceived in an open TA Instrument aluminum sample pan and was programheated from ambient to 120° C. at 10° C./min under nitrogen purge. Thecrystalline form (IS-VI) exhibited an onset temperature of melting of100.4° C., a peak temperature of melting of 101.5° C. and a heat ofmelting of 96.2 J/g.

TGA (Thermogravimetric Analysis) was measured for a representativesample of crystalline form (IS-VI), as shown in FIG. 3. The weight lossfor the sample was obtained using a TA Instruments TGA Q5000IRthermogravimetric calorimeter. The sample was analyzed as received andwas program heated from ambient to 120° C. at 10° C./min under nitrogenpurge. No weight loss was observed by TGA from ambient temperature up toand including the melting of the sample, thereby indicating thatcrystalline form (IS-VI) is a non-hydrate.

A representative sample of crystalline form (IS-VI) was subjected to DVS(Dynamic Vapor Sorption) cycling humidity conditions to determinehydgroscopicity, as shown in FIG. 4. The sample was analyzed using aSurface Measurement System DVS-1 Dynamic Vapor Sorption System. Thesample was analyzed full cycle in step mode at 25° C. from 0-90% RH in10% RH increments. The equilibration conditions set were: dm/dt of0.0007%/min, dm/dt window of 5 minutes, and minimum and maximum stagesof 15 and 360 minutes. Data was collected in 1 minute intervals.Nitrogen was used as the carrier gas. The results from the DVSmeasurements indicate that crystalline form (IS-VI) is non-hygoscopic

The results above indicate that crystalline form (IS-VI) of the compoundof formula (IS) exhibits stability to temperature and humidity, whichmakes it particularly well suited for formulation in solidpharmaceutical dosage forms.

The present invention further comprises pharmaceutical compositionscontaining crystalline form (IS-VI) with a pharmaceutically acceptablecarrier. Pharmaceutical compositions containing one or more of thecompounds of the invention described herein as the active ingredient canbe prepared by intimately mixing the compound or compounds with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending upon the desired route of administration (e.g., oral,parenteral). Thus for liquid oral preparations such as suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,coloring agents and the like; for solid oral preparations, such aspowders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations may also becoated with substances such as sugars or be enteric-coated so as tomodulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.1-1000 mg or anyrange therein, and may be given at a dosage of from about 0.01-300mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day,or any range therein. The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 1000 mg,or any amount or range thereof, of the active ingredient of the presentinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of material can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The methods of treatment described in the present invention may also becarried out using a pharmaceutical composition comprising any of thecompounds as defined herein and a pharmaceutically acceptable carrier.The pharmaceutical composition may contain between about 0.01 mg and1000 mg of the compound, or any range therein; preferably about 10 to500 mg of the compound, and may be constituted into any form suitablefor the mode of administration selected. Carriers include necessary andinert pharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of anxiety and related disorders; bipolar depressionand mania; depression; epilepsy and related disorders; epileptogenesis;glucose related disorders; lipid related disorders; migraine; obesity;pain; substance abuse or neuroprotection is required.

The daily dosage of the products may be varied over a wide range from1.0 to 10,000 mg per adult human per day, or any range therein. For oraladministration, the compositions are preferably provided in the form oftablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. An effective amount of the drug is ordinarily supplied ata dosage level of from about 0.1 mg/kg to about 1000 mg/kg of bodyweight per day, or any range therein. Preferably, the range is fromabout 0.5 to about 500 mg/kg of body weight per day, or any rangetherein. More preferably, from about 1.0 to about 250 mg/kg of bodyweight per day, or any range therein. More preferably, from about 0.1 toabout 100 mg/kg of body weight per day, or any range therein. In anexample, the range may be from about 0.1 to about 50.0 mg/kg of bodyweight per day, or any amount or range therein. In another example, therange may be from about 0.1 to about 15.0 mg/kg of body weight per day,or any range therein. In yet another example, the range may be fromabout 0.5 to about 7.5 mg/kg of body weight per day, or any amount torange therein. The compounds may be administered on a regimen of 1 to 4times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 1 Crystalline Form (IS-VI)

A 5 L 4-neck reaction flask equipped with an overhead stirrer, additionfunnel, heating mantle, temperature control unit and nitrogen outlet wascharged with(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(300 g, 1.08 moles) and 50% IPA-heptane (1500 mL; 7.36 moles). Theresulting slurry was heated to 75° C. Some solids were observed toremain in the mixture. The mixture was hot filtered under slight vacuumusing a heated filtration flask and filter paper. The flask was washedwith 50% IPA-Heptane (˜200 mL). After hot filtration the temperature ofthe reaction mixture was 62° C. Upon cooling to 46° C., over 20 min, noprecipitation was observed. Upon cooling to 30° C., no precipitation wasnoted. The resulting mixture was warmed to 40° C., and then heptane (175mL; 1.19 moles) was added over 30 minutes. After addition of theheptane, some solid was observed to develop. The heptane addition wasceased as the solids grew rapidly with a significant increase intemperature (+4° C.). Upon cooling to room temperature over 1 h, thesolids were filtered and washed with 10% IPA-Heptane (100 mL). Afterfiltration and drying, the title compound as isolated as a white solid.

Powder XRD indicated that crystalline form (IS-VI) was isolated.

EXAMPLE 2 Crystalline Form (IS-VI)

(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(9.3 kg), activated charcoal (0.3 kg), isopropanol (15.5 kg) andn-heptane (15.4 kg) were charged to a reactor. The resulting mixture washeated to reflux and filtered hot. The filter was washed with a hotmixture of isopropanol (1.7 kg) and n-heptane (1.7 kg). The filtrate wascooled to 50-54° C. and seeded with the desired polymorph form (0.02kg). The resulting mixture was stirred at 50-54° C. for 30 min.n-Heptane (14.4 kg) was then added to the mixture at 50-54° C., over 20minutes. The resulting mixture was cooled to 0-5° C. over 1 hour, thenstirred at this temperature for 2 hours. The resulting mixture wasfiltered, the filtercake washed with n-heptane and dried in vacuo at50-60° C. to yield the title compound in the desired polymorphic form(as determined by powder XRD).

EXAMPLE 3 Oral Formulation—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of thecrystalline form prepared as in Example 1 or Example 2 is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. Crystalline form (IS-VI) of a compound of formula (IS)


2. A crystalline form of a compound of formula (IS)

comprising the following powder X-ray diffraction peaks: Pos. [° 2θ.] d-spacing[Å] 13.07 6.78 18.53 4.79 19.64 4.52 19.91 4.46 21.15 4.20 22.09  4.02.


3. A crystalline form as in claim 2, comprising the following powder X-ray diffraction peaks: Pos. [° 2θ.] d-spacing[Å] 6.54 13.51  13.07 6.78 16.50 5.37 18.53 4.79 19.64 4.52 19.91 4.46 20.17 4.40 21.15 4.20 22.09 4.02 22.52 3.95 23.51 3.79 26.28 3.39 27.56 3.24 28.20 3.17 33.60  2.67.


4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline for as in claim
 1. 5. A pharmaceutical composition made by mixing a crystalline form as in claim 1 and a pharmaceutically acceptable carrier.
 6. A process for making a pharmaceutical composition comprising mixing a crystalline form as in claim 1 and a pharmaceutically acceptable carrier.
 7. A method of treating a disorder selected from the group consisting of anxiety and related disorders; bipolar depression and mania; depression; epilepsy and related disorders; epileptogenesis; glucose related disorders; lipid related disorders; migraine; obesity; pain and substance abuse; or a method of neuroprotection; comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form as in claim
 1. 8. A method as in claim 7, wherein the disorder is selected from the group consisting of depression; epilepsy and related disorders; and glucose related disorders.
 9. A method of treating of treating a disorder selected from the group consisting of anxiety and related disorders; bipolar depression and mania; depression; epilepsy and related disorders; epileptogenesis; glucose related disorders; lipid related disorders; migraine; obesity; pain and substance abuse; or a method of neuroprotection; comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim
 4. 10. A method as in claim 9, wherein the disorder is selected from the group consisting of depression; epilepsy and related disorders; and glucose related disorders.
 11. A crystalline form as in claim 1, wherein the crystalline form exhibits a peak temperature of about 101.5° C., as measured by differential scanning calorimetry.
 12. A crystalline form as in claim 1, wherein the crystalline form exhibits a heat of melting of about 96.2 J/g, as measured by differential scanning calorimetry.
 13. A crystalline form as in claim 1, wherein the crystalline form is a non-hydrate.
 14. A crystalline form as in claim 1, wherein the crystalline form is non-hygroscopic.
 15. A crystalline form as in claim 1, wherein the crystalline form is non-hygroscopic and a non-hydrate. 